Celecoxib analogs possessing a N-(4-nitrooxybutyl)piperidin-4-yl or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridin-4-yl nitric oxide donor moiety: Synthesis, biological evaluation and nitric oxide release studies

Abstract

A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) coxib prodrugs (NO-coxibs) wherein the para-tolyl moiety present in celecoxib was replaced by a N-(4-nitrooxybutyl)piperidyl 15a– b, or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl 17a– b, NO-donor moiety was synthesized. All compounds released a low amount of NO upon incubation with phosphate buffered saline (PBS) at pH 7.4 (2.4–5.8% range). In comparison, the percentage NO released was higher (3.1–8.4% range) when these nitrate prodrugs were incubated in the presence of l-cysteine. In vitro COX-1/COX-2 isozyme inhibition studies showed this group of compounds are moderately more potent, and hence selective, inhibitors of the COX-2 relative to the COX-1 enzyme. AI structure–activity relationship data acquired showed that compounds having a MeSO 2 COX-2 pharmacophore exhibited superior AI activity compared to analogs having a H 2NSO 2 substituent. Compounds having a MeSO 2 COX-2 pharmacophore in conjunction with a N-(4-nitrooxybutyl)piperidyl (ED 50 = 132.4 mg/kg po), or a N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl (ED 50 = 118.4 mg/kg po), moiety exhibited an AI potency profile that is similar to aspirin (ED 50 = 128.7 mg/kg po) but lower than ibuprofen (ED 50 = 67.4 mg/kg po).